Fluorinated Building Blocks

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What are Fluorinated Building Blocks

Case Study

How to Synthesize Fluorinated Blocks?

FAQ about Fluorinated Building Blocks

Types of Fluorinated Building Blocks

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Properties of Fluorinated Fluorinated Building Blocks

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What are Fluorinated Building Blocks?

Fluorinated building blocks are a class of organic compounds containing fluorine atoms or fluorine-containing groups, and often used in the synthesis of fluorinated compounds. They usually appear in the form of monofluoro, difluoro or trifluoro in the chemical structures, such as monofluoromethyl, difluoromethyl, trifluoromethyl. Due to the high electronegativity, small atomic radius and high polarizability of fluorine, fluorinated building blocks exhibit unique chemical, physical and biomedical properties. And when using fluorinated building blocks to construct organic fluorides, the reaction process generally does not involve the formation of new C-F bonds, the reaction conditions are mild, and the reaction is efficient. Therefore, fluorinated building blocks have been widely researched and applied.

How to Synthesize Fluorinated Blocks?

The synthesis of fluorinated structural units involves a variety of strategies aimed at introducing fluorine atoms into the organic backbone. These approaches utilize the unique reactivity of fluorine and its derivatives to build molecules with specific structural and functional properties.

Direct fluorination

Reaction of hydrocarbons with elemental fluorine (F₂) under controlled conditions. Used to synthesize perfluorinated compounds and highly fluorinated alkyl chains.

Electrophilic fluorination

Electrophilic fluorination agents selectively introduce fluorine into electron-rich sites such as olefins or aromatic rings. Commonly used for late-stage functionalization of drugs and intermediates.

Nucleophilic fluorination

Fluoride ions (F^-) act as nucleophilic reagents, replacing good-leaving groups in substitution reactions. It is used for the synthesis of alkyl fluorides and aryl fluorides, especially by halide exchange or SNAr reactions.

Fluorination by fluoroalkylation

Introduction of fluoroalkyl groups via nucleophilic or radical pathways. Key to the synthesis of trifluoromethylated and perfluoroalkylated derivatives.

Deoxyfluorination

Substitution of hydroxyl (-OH) or carbonyl groups with fluorine, usually by intermediate activation. Efficient for synthesizing alkyl fluorides and aryl fluorides from alcohols or ketones.

Radical fluorination

Fluorine radicals react with substrates to achieve selective functionalization. Promotes fluorination of complex frameworks with minimal rearrangement.

Transition metal catalyzed fluorination

Selective introduction of fluorine through C-H activation, coupling, or oxidative addition reactions. Widely used for regioselective fluorination of aromatic and aliphatic compounds.

Fluorination precursors

Addition of fluorine by direct reaction or modification of an existing fluorination support. Simplifies access to complex fluorinated molecules such as heterocycles and polymers.

Biocatalytic fluorination

Fluorinating enzymes naturally incorporate fluorine from fluoride ions into biomolecules. Used in the synthesis of fluorinated natural product analogs and fine chemicals.

Promising Synthesis Methods

Metal-induced C-F bond activation is emerging as a promising synthetic tool for the derivation of partially fluorinated structural units from readily available bulk chemicals. Hydrogen defluorination has been realized in the coordination layer of various transition metal complexes with unique mechanistic diversity.

References

Kuehnel MF., et al. (2013). "Synthesis of Fluorinated Building Blocks by Transition-Metal-Mediated Hydrodefluorination Reactions." Angewandte Chemie International Edition., 52(12), 3328-3348.

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Types of Fluorinated Building Blocks

Fluoroalkanes

In fluorinated building blocks, fluoroalkanes are a class of very valuable compounds. Due to the high electronegativity of fluorine atoms, fluoroalkanes have many unique properties, such as excellent chemical stability, surface activity, and temperature resistance.

Fluoroalkenes

Fluoroalkenes are very useful fluorinated building blocks in many chemists' synthetic work. They can prepare organic fluorides containing different groups. Fluoroalkenes have received increasing attention in organic synthesis and medicinal chemistry.

Fluoroalkynes

Fluoroalkynes are a class of dienophiles and dipoleophiles. They can be used as building blocks for the synthesis of fluorine-containing organic compounds. Fluoroalkynes can produce various metallated fluorine-containing alkenes through hydrometallation reactions.

Fluorinated Aliphatic Cyclic Hydrocarbons

Fluorinated aliphatic cyclic hydrocarbons are closed-chain hydrocarbons with properties of aliphatic compounds. They can be divided into fluorinated saturated alicyclic hydrocarbons and fluorinated unsaturated alicyclic hydrocarbons.

Aromatic Fluorocarbons

Aromatic fluorocarbons refer to a series of aromatic compounds with one or several fluorine atoms directly connected to the aromatic ring skeleton. They have many excellent properties due to the presence of fluorine, such as lipophilicity and metabolic stability.

Fluorinated Carbonyl Compounds

Fluorinated carbonyl compounds are important fluorinated building blocks in organic synthesis. They can be prepared through Diels-Alder reaction, Michael addition or Robinson annulation, and are widely used to construct alkenes, alkanes, heterocyclic compounds, etc.

Fluorinated Alcohols

Fluorinated alcohols have attracted extensive research attention due to their low boiling point, high melting point, high polarity, strong hydrogen bonding and strong solubility. A large number of fluorinated alcohols were developed and used.

Fluorinated Carboxilic Acids

The fluorinated carboxilic acids are strong acids due to the strong electronegativity of the fluorine atom. They have good heat resistance and chemical stability, do not react with general reducing agents and oxidizing agents in aqueous solution.

Fluorinated Amines

Fluorinated amines are one of the functional building blocks with high market demand in recent years. The introduction of the fluorine element weakens the basicity of amines and enhances metabolic stability. The basic nitrogen-containing groups play an important role in regulating the properties of bioactive molecules.

Fluorinated Ethers

Fluorinated ethers have good solubility and chemical stability, and can efficiently synthesize organic fluorides, which has aroused widespread interest among researchers. Currently, more and more synthetic methods have been developed for the synthesis of fluorinated.

Fluorinated Cyclic Ethers

Fluorinated cyclic ethers are low-viscosity, non-flammable, highly safe liquids with good solubility and extremely high chemical and thermal stability. They are widely used in organic synthesis reactions to obtain organic fluorides.

Fluorinated Heterocycles

The synthesis of complex bioactive molecules through fluorinated heterocyclic monomers is one of the commonly used methods in synthetic chemistry. The presence of fluorine atoms enhances the thermal stability of heterocyclic compounds.

Properties of Fluorinated Fluorinated Building Blocks

High electronegativity

Fluorine has a significant effect on the electronic environment of neighboring atoms. The property: changes the acidity or alkalinity of neighboring functional groups. Enhances hydrogen bond acceptor strength and affects molecular interactions.

Enhanced lipophilicity

This is critical in drug design because: improves membrane permeability. Improve bioavailability. Optimize binding affinity to hydrophobic active sites in proteins.

Enhanced metabolic stability

Fluorinated compounds have strong C-F bonds that resist enzymatic degradation. This property: extends the half-life of the drug. Reduces the risk of metabolic side effects.

Unique steric effect

The small size and high electron density of fluorine atoms results in unique spatial and electronic interactions in the molecular structure. This can: influence the conformation of the molecule. Control reaction selectivity in synthesis.

Thermal and chemical stability

With strong C-F bonds, fluorinated structural units exhibit excellent stability under a variety of conditions. This is particularly favorable in: high temperature reactions. Applications in materials science, e.g., fluoropolymers and coatings.

Modification of dipole moments

The high electronegativity of fluorine gives rise to a strong dipole moment when combined with carbon, thus affecting: solubility in polar or non-polar solvents. Molecular recognition in drug-target interactions.

Tunable electronic effects

Fluorine atoms can donate or withdraw electrons depending on their position in the molecule. This flexibility enables: fine-tuning of reactivity in catalytic and organic reactions. Tuning of electronic properties in functional materials.

Bio-electronic iso-exclusion

Fluorine is often used as a bioelectronic equivalent of hydrogen or hydroxyl groups in biologically active compounds and has the following roles: preservation or enhancement of biological activity. Improve selectivity and reduce off-target effects of drugs.

Product Features

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Application of Fluorinated Building Blocks

Materials Chemistry

From fluorinated building blocks, we can make organofluorine polymers, which are extraordinarily stable at temperature and chemical temperatures and are used extensively in materials chemistry. For instance, polytetrafluoroethylene, produced by addition polymerisation of tetrafluoroethylene as a fluorinated molecule, is heat and cold resistant and almost undetectable to other chemical reagents. And the perfluoroether rubber by copolymerizing perfluoroether is invulnerable to N₂O₄ medium, high temperature and low temperature, and is used as sealant.

Medicinal Chemistry

Fluorinated building blocks introduce fluorine into drug molecules, which often significantly changes the lipid solubility of the parent compound, enhances the metabolic stability of the molecule and affects its biological activity, and are widely used in the preparation of fluorine-containing drugs. At present, a large number of fluorine-containing drugs with high efficacy and low side effects have been synthesized, such as anticancer drugs, anti-inflammatory drugs, analgesics, lipid-lowering drugs, anesthetics, antidepressants, antifungal agents, diuretics, etc.

Agricultural Chemistry

The use of fluorinated building blocks to introduce fluorine into organic compounds has resulted in a wide range of agrochemicals, further improving the chemical stability and potency of agrochemicals, demonstrating that fluorinated building blocks improve the performance of their non-fluorinated counterparts. At present, fluorinated building blocks have been used to synthesize a series of insecticides, fungicides, herbicides, acaricides, plant growth regulators, rodenticides, synergists and termiticides.

Case Study

Synthesis and Applications of Trifluoroacetaldehyde Hydrazones in Organic Reactions

Trifluoroacetaldehyde hydrazones in organic synthesis Zhang D, et al. Beilstein Journal of Organic Chemistry, 2023, 19, 1741-1754.

Trifluoroacetaldehyde hydrazones (TFAH) are versatile intermediates in organic synthesis, playing a crucial role in the development of fluorine-containing compounds. Their unique structure, with a C=N linkage, imparts both electrophilic and nucleophilic properties, making them valuable for a wide range of reactions. Various studies have explored the potential of TFAH in diverse synthetic applications, from heterocyclic synthesis to asymmetric catalysis.

One of the most prominent reactions involving TFAH is its [3 + 2] cycloaddition with ethyl glyoxal, leading to the formation of 4-hydroxy-3-trifluoromethylpyrazoles. This reaction, reported by Tanaka et al., provides an efficient method for synthesizing pyrazole derivatives, which are precursors to a variety of bioactive compounds. Additionally, Wu et al. expanded the scope of TFAH by demonstrating a non-stereoselective 1,3-dipolar cycloaddition with α,β-enones, yielding multi-substituted pyrazolines and pyrazolines, which are important intermediates for drug synthesis.

Rueping et al. further advanced the chemistry of TFAH by introducing an asymmetric catalytic [6π] electrocyclization under Bronsted acid catalysis, producing enantiomerically enriched 3-trifluoromethyl-1,4-dihydropyridines. This breakthrough method offers a new platform for chiral molecule synthesis and has significant potential for future applications in asymmetric catalysis. Additionally, Zhan et al. reported an efficient and selective synthesis of CF₃-pyrazoles and CF₃-1,6-dihydropyridines via trifluoromethylation of N-allyl hydrazones, highlighting the role of TFAH in the development of fluorinated heterocyclic compounds.

In summary, trifluoroacetaldehyde hydrazones are highly reactive intermediates that have enabled the synthesis of a wide range of fluorinated heterocycles, with applications in medicinal chemistry, materials science, and catalysis. Their ability to undergo various reactions, including cycloadditions, electrocyclizations, and nucleophilic substitutions, makes them indispensable in modern synthetic chemistry.

Synthesis and Application of Fluorine-Containing sp³-Enriched Building Blocks for the Multigram Production of Fluorinated Pyrazoles and Pyrimidines

Fluorine-Containing sp3-Enriched Building Blocks for the Multigram Synthesis of Fluorinated Pyrazoles and Pyrimidines with (Hetero)aliphatic Substituents Fedinchyk A, et al. European Journal of Organic Chemistry, 2022, 2022(15), 83-95.

Fluorine-containing sp³-enriched building blocks are emerging as crucial intermediates for the synthesis of fluorinated heterocycles, particularly pyrazoles and pyrimidines, which are key components in drug discovery. The development of efficient methods for their large-scale synthesis offers valuable opportunities in medicinal chemistry. This study describes a novel multigram-scale approach to the synthesis of fluorinated pyrazoles and pyrimidines, which incorporate saturated (hetero)cyclic substituents. These fluorine-enriched building blocks, prepared from β-bromo-α,α-difluoroketones and fluorinated enaminones, have been demonstrated to meet essential criteria for drug development, including favorable LogP values, aqueous solubility, and lead-likeness according to Nelson's LLAMA tool.

The synthetic process is based on heterocyclization reactions that yield the target fluorinated heterocycles with high efficiency. The β-bromo-α,α-difluoroketones and α-fluoroketones used as intermediates are versatile compounds in both synthetic and medicinal chemistry, providing an effective platform for further functionalization and modification. The synthesis of 19 sp³-enriched fluorinated building blocks on scales up to 10 g has been achieved, which is significant for the large-scale preparation needed for drug development and other applications.

These building blocks demonstrate excellent potential for incorporation into lead compounds due to their favorable physicochemical properties and compatibility with established drug design criteria. Their use in the development of fluorinated pyrazoles and pyrimidines holds promise for advancing novel therapeutic agents, particularly in the context of targeting diseases with high unmet medical needs.

Fluorinated Molecular Building Blocks for the In-Situ Synthesis of Defect-Free KAUST-7 Membranes with Enhanced Gas Separation Properties

In-situ synthesis of KAUST-7 membranes from fluorinated molecular building block for H2/CO2 separation Lv J, et al. Journal of Membrane Science, 2022, 658, 120585.

Fluorinated molecular building blocks are integral to the synthesis of high-performance materials, particularly in the development of advanced membranes for gas separation applications. In this study, a fluorinated precursor, NiNbOF5, was employed in an innovative in-situ synthesis method to produce defect-free KAUST-7 membranes on α-Al2O3 substrates. This process utilizes water as a green solvent, avoiding the corrosive effects of traditional high-concentration hydrofluoric acid (HF) treatments, which are known to damage the support materials.

The synthesis involves carefully controlling the pH of the reaction medium, a critical factor for the successful formation of the KAUST-7 membrane. The fluorinated NiNbOF5 precursor forms a stable interaction with the α-Al2O3 surface, which promotes the homogeneous nucleation of the 2D Ni(II)-pyrazine layers essential for KAUST-7 membrane formation. The optimized method yields membranes with excellent structural integrity, as confirmed by XPS and FT-IR analyses, which suggest the formation of AlFxOy or Alx species that act as linkers between the 2D metal-organic framework (MOF) and the support surface.

The resultant KAUST-7 membranes demonstrated superior gas separation properties. At 25°C and 1 bar pressure, the membrane exhibited a high H₂/CO₂ selectivity of 17.7 and a H₂ permeance of 2.2 × 10−7 mol m−2 s−1 Pa−1. These properties remained stable even at elevated temperatures of 120°C, demonstrating the robustness of the membrane. The approach offers a scalable and efficient route for fabricating high-performance membranes, with significant potential in industrial gas separation applications.

Fluorinated Benzothiadiazole as a Modifiable Acceptor Block in Rhodium(III)-Catalyzed Synthesis of Polyheteroaromatic D-A Systems

Rhodium(III)-catalyzed Construction of D-A Type Polyheteroaromatics with Fluorinated Benzothiadiazole as a Modifiable Acceptor Block Gribanov PS, et al. Asian Journal of Organic Chemistry, 2022, 11(12), Pages 324-329.

Fluorinated benzothiadiazole (BTD) has emerged as a versatile building block for the synthesis of novel donor-acceptor (D-A) polyheteroaromatic systems, with potential applications in organic electronics and materials science. A recent study has developed an efficient, Rhodium(III)-catalyzed pathway for the regioselective [4+2] annulation of N-(pivaloyloxy)-benzamides with 4-ethynyl-5,6-difluoro-7-(p-methoxyphenyl)-2,1,3-benzothiadiazole, followed by an aromatization and Suzuki coupling sequence. This approach facilitates the construction of fluorinated polyheteroaromatic D-A molecules, where the fluorinated BTD serves as a modifiable acceptor block.

The key innovation in this synthesis lies in the divergent modification of the BTD acceptor block. By leveraging the distinct reactivity of arylboronic acids (ArB(OH)2) versus arylboronic pinacol esters (ArBPin), the researchers demonstrated ortho-selective C-F activation of the fluorinated BTD moiety under Suzuki coupling conditions. This strategy enables the stepwise modification of the BTD acceptor block, affording a new family of D1-π-A-D2 systems in good yields. The process is notably catalyzed by Pd, utilizing a C-F bond activation mechanism assisted by an isoquinoline ring, marking a significant advancement in the selective functionalization of fluorinated aromatic compounds.

This synthetic methodology opens new avenues for the design of highly functionalized polyheteroaromatic systems with tunable electronic properties, enabling their use in applications such as organic semiconductors, photovoltaic devices, and light-emitting diodes (LEDs).

Trifluoromethylated Hydrazonoyl Halides as Key Intermediates for the Synthesis of Fluorinated Heterocycles and Bioactive Compounds

Trifluoromethylated Hydrazonoyl Halides in organic synthesis Zhang D, et al. Beilstein Journal of Organic Chemistry, 2023, 19, 1741-1754.

Trifluoromethylated hydrazonoyl halides are highly reactive intermediates with significant potential in synthetic chemistry, particularly for the preparation of fluorinated heterocycles. These compounds, which contain a reactive 1,3-dipole, can be readily transformed into nitrile imines under basic conditions. They have proven to be valuable building blocks in the synthesis of a wide range of heterocyclic compounds, many of which feature fluorine or fluorine-containing groups that are of considerable interest in medicinal chemistry and material science.

A commonly employed synthetic route involves the reaction of trifluoroacetaldehyde hydrazones with N-chloro- or N-bromosuccinimide, or alternatively with trichloroisocyanuric acid (TCCA), to generate trifluoromethylated hydrazonoyl halides. These intermediates have shown excellent versatility, undergoing reactions with olefins, acetylenes, β-diketones, β-keto esters, and various other nucleophiles to yield trifluoromethylated compounds in high yields.

Notably, these hydrazonoyl halides can undergo [3+2] cycloadditions with thioketones, thiochalcones, and other dipolarophiles, leading to the formation of trifluoromethylated 1,3,4-thiadiazoles and related heterocycles. Additionally, their reaction with mercaptoacetaldehyde and mercaptocarboxylic acids results in the synthesis of fluorinated 1,3,4-thiadiazines via a [3+3] annulation. These reactions highlight the utility of trifluoromethylated hydrazonoyl halides in generating complex, fluorine-substituted heterocycles with potential pharmaceutical applications.

Furthermore, trifluoromethylated pyrazoles, synthesized via [3+2] cycloadditions with fluorinated nitrile imines, have gained attention for their use in medicinal products and pesticides. The versatility and broad reactivity of trifluoromethylated hydrazonoyl halides make them invaluable intermediates for the development of new bioactive compounds and fluorinated materials.

FAQ about Fluorinated Building Blocks

Q1 What sizes or purities of fluorinated blocks does Alfa Chemistry offer?

We offer a wide range of fluoroblocks, typically with purities greater than 95%. Specific products can be customized to meet customer needs, including mass-produced and specially functionalized fluoroblocks.

Q2 How do I choose the right fluoroblocks?

The following factors should be taken into consideration when selecting a suitable fluorine-containing block: (1) The structure and functional requirements of the target compound. (2) Required chemical reaction conditions (e.g., temperature, solvent). (3) Purity and stability requirements of the product. (4) Specific requirements for performance in the application area (e.g., optimization of pharmacokinetic properties in drugs).
If you are unsure of your choice, our technical team can provide you with expert advice.

Q3 Do Alfa Chemistry's fluorinated blocks support customization?

Yes, we do! We support the customization of fluorine-containing blocks, covering the introduction of specific functional groups, multi-step synthesis, and large-scale production. Customers can provide specific information about their target compounds or design ideas, and we will develop customized blocks according to their needs.

Q4 How do I store fluoroblocks?

Most of the fluorobricks need to be stored under dry, light-protected, low temperature (e.g., 2-8 °C or frozen conditions) to ensure their stability. Specific storage conditions can be found on product labels or technical instructions.

Q5 How to get the technical information (e.g., MSDS or charts) of fluorine-containing blocks?

You directly contact our customer service team to request. We provide detailed MSDS, safety guidelines, and nuclear magnetic resonance (NMR) and mass spectrometry (MS) data.

Q6 Are there any special requirements for the transportation of fluorinated blocks?

Some fluoroblocks may be hazardous chemicals and need to be transported in accordance with relevant regulations. We will choose the appropriate mode of transportation according to the nature of the product and provide customers with standardized packaging.

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